Conformational dynamics of Mycobacterium tuberculosis M13 metalloprotease Zmp1 and how it interacts with potential substrates
Session Number
Project ID: BIO 10
Advisor(s)
Nicky Bayhi; The University of Chicago
Dr. Wei Jen Tang; The University of Chicago
Discipline
Biology
Start Date
19-4-2023 10:35 AM
End Date
19-4-2023 10:50 AM
Abstract
Tuberculosis (TB) is caused by a bacterium known as Mycobacterium tuberculosis (Mtb). During infection, Mtb secretes a variety of proteins to confuse the host's immune system including Zinc Metalloprotease 1 (Zmp1). Zmp1 inhibits phagosome maturation and host cell inflammation activation, both of which are vital during M. tuberculosis virulence. It has a hollow catalytic core in which peptides bind and are unfolded and repositioned for proteolysis. But it is unclear how Zmp1 does this, or what substrates it cleaves. To investigate these questions, we applied all- atom molecular dynamics (MD) simulations to characterize the conformational heterogeneity of Zmp1. In addition to the expected “hinge” opening of domain-1 (D-1) swinging away from domain 2 (D-2), we observed D-1 rotate, or “grind,” against D-2, and characterized the structural basis of this motion. We went on to use coarse-grained simulations to illustrate how various known substrates of Zmp1 are repositioned and unfolded inside this protein. Together, these studies teach us about how this enzyme works, and lay the foundation for future efforts to identify physiologically-relevant substrates and to engineer Zmp1 variants with new functions.
Conformational dynamics of Mycobacterium tuberculosis M13 metalloprotease Zmp1 and how it interacts with potential substrates
Tuberculosis (TB) is caused by a bacterium known as Mycobacterium tuberculosis (Mtb). During infection, Mtb secretes a variety of proteins to confuse the host's immune system including Zinc Metalloprotease 1 (Zmp1). Zmp1 inhibits phagosome maturation and host cell inflammation activation, both of which are vital during M. tuberculosis virulence. It has a hollow catalytic core in which peptides bind and are unfolded and repositioned for proteolysis. But it is unclear how Zmp1 does this, or what substrates it cleaves. To investigate these questions, we applied all- atom molecular dynamics (MD) simulations to characterize the conformational heterogeneity of Zmp1. In addition to the expected “hinge” opening of domain-1 (D-1) swinging away from domain 2 (D-2), we observed D-1 rotate, or “grind,” against D-2, and characterized the structural basis of this motion. We went on to use coarse-grained simulations to illustrate how various known substrates of Zmp1 are repositioned and unfolded inside this protein. Together, these studies teach us about how this enzyme works, and lay the foundation for future efforts to identify physiologically-relevant substrates and to engineer Zmp1 variants with new functions.